Anavex Life Sciences Corp (AVXL)

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See this recent article about blarcamesine effectiveness in treating multiple CNS disorders.

[CNS Drugs.](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#) 2023; 37(5): 399--440.

Published online 2023 May 11. doi: [10.1007/s40263-023-01007-6](https://doi.org/10.1007%2Fs40263-023-01007-6)

PMCID: PMC10173947

PMID: [37166702](https://pubmed.ncbi.nlm.nih.gov/37166702)

# Targeting Sigma Receptors for the Treatment of Neurodegenerative and Neurodevelopmental Disorders

.....Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. ...

### ANAVEX2-73 (Blarcamesine)

Blarcamesine (ANAVEX2-73; Fig. [?Fig.2)2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/figure/Fig2/)) is a s1R receptor agonist with an affinity of 860 nM (IC50) [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)] developed for treating AD. Blarcamesine also has agonist activity at the muscarinic M1 receptor, and the NMDA receptor with affinities of 5 and 8 µM, respectively [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)].

#### Alzheimer's Disease

Pre-clinical studies have shown that blarcamesine can reverse scopolamine's long-term amnesic effects in mice [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)]. Furthermore, blarcamesine can reverse the effect of learning deficits in mice injected with Aß25--35 [[222](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR222)--[224](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR224)]. Blarcamesine given to mice injected with Aß25--35 restored respiration rates in hippocampal mitochondria and reduced lipid peroxidation levels. Blarcamesine could also prevent tau-hyperphosphorylation and amyloid-ß (1--42) generation in mouse models of AD [[223](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR223)]. Furthermore, indicators of increased toxicity, including Bax/Bcl-2 ratio and cytochrome C release into the cytosol, were reduced [[224](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR224)]. Blarcamesine has protective effects in _Caenorhabditis elegans_ and cell culture models of AD by enhancing autophagic flux and increasing proteostasis [[65](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR65)].

A phase 1 clinical study in healthy male volunteers showed that doses up to 50 mg were well tolerated, with no serious adverse events reported in a poster at the CNS summit in 2014 [[225](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR225)]. At 60 mg, three out of four subjects presented dose-limiting CNS symptoms (dizziness and headache). The study concluded with pharmacokinetic analysis showing extensive biotransformation of blarcamesine to AV19-144 (the bioactive form of the drug) with assumed linear pharmacokinetics after single oral dosing of 1 to 60 mg blarcamesine [[225](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR225)].

A biomarker analysis, phase 2a study ([NCT02244541](https://clinicaltrials.gov/ct2/show/NCT02244541)), that include some exploratory study into the benefits of blarcamesine, where blarcamesine was administered over 57 weeks, showed a significant reduction in cognitive decline [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)]. When the study was extended to 265 weeks ([NCT02756858](https://clinicaltrials.gov/ct2/show/NCT02756858)), there was confirmation of this prevention of decline at 148 weeks with analysis of blood concentrations of blarcamesine and its metabolite AV19-144, showing that those with high concentrations of blarcamesine had improved therapeutic responses of 78% and 88% in adjusted MMSE and adjusted AD cooperative study--activities of daily living (ADCS--ADL), respectively, relative to the low/medium concentrations of blarcamesine.

Furthermore, genomic analysis also indicated the significant effects of biomarkers on clinical outcomes of blarcamesine. Two patients showed an exceptional therapeutic response at 148 weeks. Both subjects had s1R wild type and a high mean concentration of blarcamesine in plasma, with a baseline MMSE > 20 [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)].

The study of biomarkers that predict the potential therapeutic outcome of a drug is especially useful in a disease with such heterogeneity as AD [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)]. The ApoE e4 genotype alone lacks predictive power since only approximately 25% of people carry this genotype. The study discussed above identified that patients with a baseline MMSE greater than 20 who had the s1R wild type with a high mean blarcamesine serum concentration and _ApoE3_ alleles had significantly better outcomes in the ADCS--ADL. The _SIGMAR1_ Q2P variant, having a baseline MMSE score lower than 20 and a low mean serum concentration of blarcamesine were predictive of poor outcomes in the ADCS--ADL [[226](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR226)].

Blarcamesine is undergoing further phase 2b/3 clinical trials (ongoing: [NCT04314934](https://clinicaltrials.gov/ct2/show/NCT04314934); completed with data yet to be published: [NCT03790709](https://clinicaltrials.gov/ct2/show/NCT03790709)). The results of these clinical trials will be interesting, given the promise blarcamesine has shown in the pre-clinical studies.

#### Multiple Sclerosis

Blarcamesine increased the proliferation of oligodendrocyte progenitor cells to myelin sheath-producing oligodendrocytes in a s1R-dependent manner and protected them from excitotoxic insults [[227](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR227)]. There are no currently listed clinical trials for blarcamesine in MS on [www.clinicaltrials.gov](http://www.clinicaltrials.gov/).

#### Rett Syndrome

Long-term administration of blarcamesine to mice deficient in MeCP2 restores physiological and neurological abnormalities that mimic the human Rett syndrome, including ameliorating motor and acoustic startle deficits and reversing expiratory apnoea [[228](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR228)]. Several s1R-related mechanisms could benefit the neurological and motor symptoms seen in this and other models of Rett syndrome. Enhancement of calcium homeostasis via s1R shuttling of calcium to the mitochondria leads to improved mitochondrial function and the activation of autophagy via s1R activation, resulting in a reduction of misfolded proteins and fewer damaged organelles or the restoring/upregulation of BDNF [[65](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR65), [228](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR228), [229](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR229)]. This leads to potential improvements in synaptic function in multiple brain regions.

Blarcamesine is currently in phase 2/3 clinical trials ([NCT03758924](https://clinicaltrials.gov/ct2/show/NCT03758924), [NCT03941444](https://clinicaltrials.gov/ct2/show/NCT03941444) and [NCT04304482](https://clinicaltrials.gov/ct2/show/NCT04304482)). Blarcamesine has shown positive results in a phase 2 clinical trial ([NCT03758924](https://clinicaltrials.gov/ct2/show/NCT03758924)) in female patients diagnosed with Rett syndrome (positive _MeCP2_ gene mutation), meeting both primary and secondary endpoints with no reported serious adverse events (press release) [[230](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR230)]. In another phase 3 ([NCT03941444](https://clinicaltrials.gov/ct2/show/NCT03941444)) clinical trial the primary and secondary endpoints were met with significant improvements versus placebo in the clinical global-impression of improvement scale (CGI-I); the anxiety, depression and mood scale (ADAMS); and drug exposure-dependent response of the Rett Syndrome Behaviour Questionnaire (RSBQ), all with a low incidence of adverse events (press release) [[230](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR230)]. It is important to note that the data available from these studies has not been peer reviewed and formally published. There are further ongoing phase 3 studies organized by Anavex Life Sciences ([NCT04304482](https://clinicaltrials.gov/ct2/show/NCT04304482)). However, while the data look promising, it will be important to see some independent studies with peer-reviewed results to fully assess the efficacy and safety of blarcamesine for Rett syndrome treatment.

### ANAVEX3-71

ANAVEX3-71 (AF710B) (Fig. [?(Fig.2)2](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/figure/Fig2/)) is an agonist at the muscarinic M1 receptor and s1R, and the second drug developed by for AD treatment. ANAVEX3-71 has an affinity for the s1R of 1.3 nM and an affinity for the s2R of 10 µM [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62)]. The affinity for the M1 receptor is approximately 0.05 nM. ANAVEX3-71 also has affinities for the µ opioid receptor and serotonin receptor (approximately 10 µM for each) [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62)].

#### Alzheimer's Disease

Given the complex pathology of AD, it is of interest that a drug such as AF710B may interact with multiple target sites to have a beneficial effect in AD [[52](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR52)].

Pre-clinical studies have shown ANAVEX3-71 to be worthy of further study. AF710B has been shown to modify the disease-defining hallmarks of AD in transgenic (3×Tg-AD) mice, such as cognitive deficits, amyloid and tau pathologies, and beneficial effects on mitochondrial dysfunction and neuroinflammation [[62](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR62), [231](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR231)].

Phase 1 clinical trials ([NCT04442945](https://clinicaltrials.gov/ct2/show/NCT04442945)) in healthy individuals have been reported on Anavex Life Sciences' website, suggesting that in healthy volunteers, 5--200 mg daily had no serious adverse events. The pharmacokinetics of ANAVEX3-71 (serum concentration of AF710B) was also proportional to the dose for doses up to 160 mg. Furthermore, there were no clinically significant electrocardiogram (ECG) parameters throughout the study (press release) [[232](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/#CR232)].

There are no further registered ([www.clinicaltrials.gov](http://www.clinicaltrials.gov/)) ongoing clinical trials with ANAVEX3-71. However, Anavex states on its website that they plan further phase 2 clinical trials. More independent studies are required. However, pre-clinical data on ANAVEX3-71 suggest it could be useful in treating dementia and AD.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173947/